The synthesis of aldehydes and ketones are ubiquitous processes in industrial and academic preparation of organic compounds (drugs, fragrances, food additives etc). Current methods require stoichiometric metal oxidants or are catalyzed by expensive and potentially toxic transition metals. In addition, the oxidative resolution of chiral racemic or meso compounds is of great interest due to the role of enantio-pure alcohols as synthetic precursors and active ingredients. A serious limitation of these methods is that heavy metal containing reagents are used, leading to undesirable toxic waste which must either be deposited or undergo costly treatment. The search for more environmentally friendly methods of preparing aldehydes, ketones and of resolving alcohols is of great importance.
One known solution is the use of THE achiral nitroxyl compound 2,2,6,6-tetramethylpiperidine N-oxyl (TEMPO) (FIG. 1, compound (2)) as an organic catalyst in combination with a stoichiometric oxidant such as household bleach. TEMPO is considered to be a low environmental burden type organic oxidation catalyst as compared with heavy metals. PCT International Patent Application WO 2006/105354 discloses a process for selective oxidation of a primary alcohol of a triterpenoid to the corresponding aldehyde, using TEMPO derivatives. U.S. Pat. No. 5,821,374 (corresponding to EP 775684) discloses a process for the oxidation of alcohols using TEMPO derivatives. Shibuya, M. et al. J. Org. Chem. 2008, 73, 4750-4752 discloses a process for the oxidative rearrangement of tertiary allylic alcohols using TEMPO-based oxoammonium salts. Shibuya, M. et al. Org. Lett. 2008, 10(21), 4715-4718 discloses a process for catalytic oxidative rearrangement of tertiary allylic alcohols to β-substituted α,β-unsaturated ketones using a TEMPO/NalO4—SiO2 catalyst. However, TEMPO derivatives are relatively unreactive towards secondary alcohols (Shibuya, M. et al. J. Org. Chem. 2009, 74, 4619-4622). This is due to the nitroxyl being flanked by sterically demanding methyl groups. Furthermore, TEMPO has a stability problem and tends to decompose (Scheme 1). In addition, TEMPO is not chiral. Most known chiral nitroxyl compounds share the sterically demanding design and reactivity profile of TEMPO.

One solution would be to introduce a small group (a hydrogen) on the carbon next to the nitroxyl group. However such compounds are inherently unstable, since upon oxidation tautomerization occurs leading to the nitrone which is no longer catalytically active (Scheme 2). Indeed, a recent review (J. M. Bobbitt and C. Bruckner, Organic Reactions vol. 74, Chapter 2) discloses: “These nitroxides are prepared by oxidation of secondary amines that contain no hydrogen on the alpha-carbon. If the amines carry alpha-hydrogens the oxidation products are nitrones, not free radical nitroxides.”

One class of compounds, the bicyclic small ring compounds such as 2-azadamantan-N-oxyl (AZADO) and the related 1-methyl AZADO (Me-AZADO) (FIG. 1), offers stability to nitroxyl compounds comprising alpha-hydrogens. The stability results from the inability to form double bond containing nitrones to a bridge head atom (an example of Bredt's rule). Dupeyre, R. M. et al., Tetrahedron, 1978, 34, 1501-1507 discloses AZADO and its derivatives, and their characterization. Shibuya, M. et al. (i) J. Org. Chem. 2009, 74, 4619-4622; (ii) J. Am. Chem. Soc. 2006, 128, 8412-8413; and (iii) US Patent Application No. 2007/0232838 (corresponding to EP 1775296) describe the use of AZADO and Me-AZADO as organocatalysts for oxidation of primary and secondary alcohols. US Patent Application No. 2009/0124806 discloses a process for preparing a carboxylic acid from a primary alcohol, using an alkali metal chlorite as a co-oxidizing agent and an oxoammonium salt based pm AZADO and its derivatives. US Patent Application No. 2010/0311977 discloses a method for producing AZADO derivatives of formula (1) by cyclizing a compound of formula (2). The non-racemic members of this family have a very narrow scope in kinetic resolutions of racemic alcohols. In addition, the preparation of AZADO-based compounds is cumbersome and based on expensive starting materials.
Tomizawa, M. et al. Organic Letters, 2009, Vol. 11(8), 1829-1831 discloses chirally modified AZADO compounds and their use in resolving racemic secondary alcohols.
Graetz, B. et al., Tetrahedron: Asymmetry, 2005, 16, 3584-3598 discloses C2-symmetric nitroxides and their use as enantioselective oxidants of alcohols.
9-azabicyclo[3.3.1]nonane N-oxyl (ABNO, FIG. 1), is a bicyclic type nitroxyl radical structurally homologous to AZADO. The utility of ABNO as a radical trapping agent, a radical generator and a spin labeling agent has been previously reported by Nelsen, S. F. et al., J. Am. Chem. Soc., 1978, 100, 7876 and Momose, T. et al., J. Chem. Soc., Perkin Trans., 1, 1997, 1307. US Patent Application No. 2008/0221331 describes the use of ABNO as an alcohol oxidation catalyst. Shibuya et al., J. Org. Chem. 2009 describes a process for preparing ABNO and its utility as an alcohol oxidizing agent. PCT International Patent Application Nos. WO 2009/145323 (corresponding to US 2011/153076) and WO 2008/117871 describe methods of oxidizing alcohols with ABNO derivatives. These compounds suffer from the same disadvantages as AZADO-based compounds.
Blinco, J. P., Bottle, S. E. et al. Eur. J. Org. Chem., 2007, 4638-4641 discloses an azaphenalene-based fused aromatic nitroxide TMAO [1,1,3,3-tetramethyl-2,3-dihydro-2-azaphenalen-2-yloxyl], and its use as a fluorescent agent. A later publication from the same authors (J. Org. Chem. 2008, 73, 6763-6771) describes cyclic nitroxides from four different structural classes (pyrrolidine, piperidine, isoindoline and azaphenanlene) and studies on their redox potentials. PCT International Application No. WO 2007/124543 discloses fused aromatic nitroxide compounds and their use as pro-fluorescent agents. Rychnovsky, S. D. et al., J. Org. Chem., 1996, 61, 1194-1195 discloses enantioselective oxidation of secondary alcohols using a chiral nitroxyl (N-oxoammonium salt) catalyst. All of the compounds disclosed in the aforementioned publications contain alkyl, aryl, arylalkyl or heteroalkyl substituents at the alpha-positions adjacent to the nitroxyl moiety.
Given the widespread importance of aldehydes, ketones and optically active alcohols in the chemical and pharmaceutical fields, efficient reagents and synthetic methods that avoid the shortcomings of prior art processes are highly desirable.